Ophthalmic composition

ABSTRACT

The present invention is directed to an ophthalmic composition in the form of a topical aqueous solution consisting essentially of 
     an ophthalmologically active agent containing basic groups, 
     an ion sensitive, hydrophilic polymer containing acidic groups in an amount of 0.004 to 1.5% by weight, 
     at least one salt selected from the group of inorganic salts and buffers in a total amount of from 0.01 to 2.0% by weight, 
     and optionally a wetting agent and a preservative, the ratio between salt and polymer being such that the solution exhibits a viscosity of less than 1000 mpas, and the pH of the solution is 4.0 to 8.0. The composition contains a sufficient amount of polymer to provide for a controlled absorption of the drug into the eye, its viscosity having been reduced to provide for better handling characteristics.

BACKGROUND OF THE INVENTION

The present invention relates to an ophthalmic composition in the formof a topical aqueous solution for human and veterinary use, as well asthe use of the solution, especially for the treatment of glaucoma andocular hypertension.

It is well known to use polymers alone or in combination with otherpolymers for the preparation of ophthalmic pharmaceuticals andartificial tear compositions. The inclusion of the polymer aims atincreasing the viscosity of the composition so as to provide for alonger contact time with the cornea of the eye, and, for example, inconnection with ophthalmic drugs, to provide for a sustained release ofthe drug into the eye.

For example, the U.S. Pat. Nos. 5,075,104 and 5,209,927 relate to anophthalmic gel composition and an ophthalmic liquid composition,respectively. The first mentioned composition includes 0.25 to 8% byweight of a carboxy vinyl polymer (polymer of carbomer type), the latter0.05 to 0.25% by weight, resulting in viscosities of the compositionsranging from 15000 to 300000, or 10 to 20000, respectively.

In the publication WO 93/17664 high viscosity, polymer containingophthalmic compositions are disclosed containing, in combination,carboxy vinyl polymers of the carbomer type, and cellulosic polymers.According to this disclosure lower polymer concentrations can be usedwhile still achieving the desired higher viscosity. A wide range for theconcentration of polymers is given, the broadest range indicated being0.05 to 3% by weight of carbomer, and 0.05 to 5.0% by weight ofcellulose polymer. A similar two-polymer system is described in theWO-publication WO 91/19481, the system being such which gels whenexposed to the pH and temperature conditions of the eye surface. In thesaid publication, an inclusion of up to 0.9% of salt is contemplated forthe adjustment of the viscosity.

There is also a number of publications relating to pharmaceuticallyactive ophthalmic compositions containing various polymers, i.a. carboxyvinyl polymers, at various concentrations. As tonicity regulatingagents, usually non-ionic polyols are suggested so as not to interferewith the gel structure (WO 93/00887, WO 90/13284). In the publicationInt. J. Pharm. 81 (1992) 59-65, aqueous compositions containing timololmaleate and 0.6% polyacrylic acid (MW 250,000), as well as the salt oftimolol base with 0.6% polyacrylic acid are described, containingmannitol as tonicity regulator. The viscosity measured at low shearrates is indicated as being 45 centipoise.

In the DE-patent specification 28 39 752 ophthalmic gel compositions aredescribed containing carboxy vinyl polymers in an amount of 0.05 to 5.0%by weight and exhibiting viscosities of 1000 to 100,000 centipoise.According to this disclosure, a small amount of sodium chloride from0.001 to 0.5% by weight is added in order to prevent the gel frombreaking down on the surface of the eye (see column 4, lines 41 ff).

SUMMARY OF THE INVENTION

The present invention is based on the discovery that the beneficialeffect of ophthalmic compositions of the above type containing viscosityenhancing agents, is due to the concentration of the polymer present inthe composition, rather than on the viscosity thereof. Thus one objectof the invention is to provide an ophthalmic composition with asufficiently high concentration of polymer to control the formation ofthe polymer film on the cornea of the eye, but which composition isstill fluid enough for ocular topical application. A further object ofthe invention is to provide an easy-to-use eye drop formulation withimproved patient compliance.

According to the invention it has now been shown that by raising theconcentration of the polymer over a value where the composition normallyis a gel rather than a liquid and by simultaneously lowering theviscosity thereof, it is possible to obtain a desired beneficial effectof the active agent in the eye, while simultaneously reducing anydiscomfort in the patient's eye, as compared to the administration of acomposition in gel form. The unbroken and even polymer film still beingformed on the eye facilitates the binding and retaining of water on thesurface of the eye, and thus provides for an additional wetting effectwhile providing for a better contact and thus a controlled absorption ofactive agent into the eye.

According to the invention we have shown that it is the amount ofpolymer in the composition, rather than the viscosity of the compositionas such, which are important from the point of view of obtaining goodabsorption of drug into the eye. This is especially evident from thetests described below. In the FIG. 3 it is shown, for example, that byusing the same amount of polymer, in compositions that have differentviscosities, the compositions provide for substantially the sameabsorption. According to the state of the art one would, however, hadexpected the composition with the higher viscosity to provide for thehigher absorption. These results are supported also by the resultspresented in the FIG. 4, which show that compositions, which containdifferent amounts of polymer, but have the same viscosities and pH's,the absorption is stronger form the composition with the higher polymerconcentration.

A further important beneficial effect is achieved by using, according tothe invention, an ophthalmologically active agent which contains basicgroups, such as amine groups. Such a basic agent participates in an ionexchange reaction or salt formation with a polymer containing acidgroups, such as polyacrylic acid polymer. The increased retaining ionicforces between the polymer and active agent provides for a furtherimproved delivery of the active agent. Due to the fact that the basicdrug is well retained by the polymer, the dosage can be lowered and/orthe daily number of administration of the drug can be reduced, ifdesired, without the loss of activity, and consequently the side effectscan be reduced as well.

The present invention thus provides an ophthalmological composition in aliquid, easy-to-use form which provides for both an increased andprolonged absorption of active agent into the eye. The invention thusmakes it possible to treat e.g. glaucoma and ocular hypertension using aonce-a-day-only or less frequent regimen for administering theophthalmological active agent and to lower the dosage clearly below thedosages presently in use.

More specifically, the object of the invention is an ophthalmologicalcomposition in the form of a topical aqueous solution consistingessentially of (%:s are of the total composition)

an ophthalmologically active agent containing basic groups,

an ion sensitive, hydrophilic polymer containing acidic groups in anamount of 0.004 to 1.5% by weight,

at least one salt selected from the group of inorganic salts and buffersin a total amount of from 0.01 to 2.0% by weight,

a wetting agent in an mount of 0 to 3.0% by weight,

a preservative in an mount of 0 to 0.02% by weight, and water,

the ratio between salt and polymer components being such that thesolution exhibits a viscosity of less than 1000 mPas, and the pH of thesolution is 4.0 to 8.0.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of viscosity versus shear rate of the solutionsdescribed in Examples 1-3 herein;

FIG. 2 is a graph of viscosity versus shear rate of the solutionscompared in Study 1 described herein;

FIG. 3 is a bar graph of concentration versus absorption time of thesolutions compared in Study 1 described herein;

FIG. 4 is a bar graph of concentration versus absorption time of thesolutions used in study 4 described herein;

FIG. 5 is a bar graph of concentration versus absorption time of thesolutions used in study 5 described herein.

FIG. 6 is a graph of viscosity versus shear rate of a solution inaccordance with Example 1 taken at various times after storage at roomtemperature.

DETAILED DESCRIPTION OF THE INVENTION

The ion-sensitive hydrophilic polymer to be used according to theinvention contains acid groups, and is typically a carboxy vinylpolymer, or hyaluronic acid. Typical representatives of carboxy vinylpolymers are the polyacrylic acid polymers, known as carbomers.Carbomers are available at different molecular weights, typicallyranging from e.g. 450.000 to 4.000.000, and sold under the trade nameCarbopol, e.g. Carbopol 907, 910, 934, 934P, 940, 941, 971, 971P, 974,974P, 980, and 981, preferably Carbopol 941 and 981.

The polymer is preferably used in an amount of 0.01 to 0.8, morepreferably 0.01 to 0.4, and advantageously 0.04 to 0.4% by weight.

According to the invention it has been established that it is favourableboth from the view point of efficacy of the product in the target site,and of ease of application, to reduce the viscosity of the compositionto a level of less than 1000 centipoise, suitably less than 800 mPas,when measured at 25° C. with a Brookfield LVDV-III type viscometer at ashear rate D of 1.1 s⁻¹. This object is achieved by adding to thecomposition a salt and/or a buffer in the specified amount, preferablyin an amount of 0.01 to 1.5% by weight. As viscosity decreasing saltsand buffers the following may be mentioned: sodium chloride, potassiumchloride, sodium phosphates (monobasic and dibasic), sodium borate,sodium acetate, sodium citrate, equivalents or mixtures thereof. In caseno salts are added, a formulation with an unacceptably high viscosity isobtained. - It is to be noted that the composition according to theinvention still exhibits favourable non-newtonian properties whenapplied to the eye surface, despite the addition of salts.

For some purposes, for example for appearance and storage purposes, theuse of a buffering salt is preferred to the use of e.g. sodium orpotassium chloride as the viscosity reducing agent.

The pH of the composition is suitably from 5.0 to 8, preferably from 6.5to 8.0. The pH of the composition is according to the invention adjustedsolely by means of the amounts used of acidic polymer and basic activeagent, respectively, and in such cases no additional pH-regulatingagents are needed. This in turn means that the process for manufacturingthe composition can be simplified.

The ophthalmologically active agent is advantageously an antiglaucomaagent, a sympathomimetic agent, a sympatholytic agent, such as aβ-blocker, carbonic anhydrase inhibitor, or an antibiotic,antiinflammatoric, antiallergic agent, etc. containing a basic group, ora combination thereof. Thus according to the invention, the eye drugscontemplated may contain a primary, secondary or tertiary amino group ororganoammonium or amidine attached to a chain or a ring, or a nitrogenatom(s) can be a part in various basic heterocycles, such as imidazole,imidazoline, pyridine, piperidine or piperazine. Preferably an agentactive against glaucoma or effective in the treatment of increasedintraocular pressure is used. A particularly preferred group ofcompounds is comprised of β-blocking agents having a secondary aminefunction such as betaxolol, carteolol, levobunolol, metipranolol,pindolol, propranolol and timolol in base form. An especiallyadvantageous mode of the invention is such where timolol is used as itseasily crystallizable S-timolol hemihydrate.

Other typical examples of basic drug molecules useful in eye therapyinclude tobramycin and norfloxacin (antimicrobial, antibacterial),cyclopentolate, tropicamide, atropine, phenylephrine, metaoxedrine(anticholinergic, mydriatic), pilocarpine, carbacol, ecothiopate(cholinergic), adrenaline, dipivefrin, dopamine (adrenergic),naphazoline, tetryzoline (vasoconstrictor), verapamil, nifedipine(vasodilator), apraclonidine, clonidine, medetomidine (α₂ -agonist),sezolamide (carbonic anhydrase inhibitor), cetirizine (antihistamine),as such or in their ester and prodrug forms.

Especially contemplated in the invention is the use of a β-blockingagent, such as S-timolol, especially in the from of the hemihydrate, asthe only drug, or as combined with e.g. the base form of pilocarpine.

The amount of active agent in the final composition may vary, such asbetween 0.001 to 5% by weight, usually, however, between 0.01 to 0.5% byweight, and typically between 0.1 and 0.5% by weight, especially in thecase of S-timolol hemihydrate.

According to an advantageous embodiment of the invention, thecomposition contains in addition, in order to enhance the wetting effectthereof, a wetting agent, preferably a polyhydric alcohol, such asglycerol. The amount of wetting agent is generally at the most 3.0, suchas of the order of 0.5 to 3.0% by weight.

As preservatives, e.g. benzalkonium chloride, benzyl alcohol, mercurysalts, thiomersal, chlorhexidine or the like, as such or in combination.The amount of preservative usually lies in the range of 0 to 0.02% byweight.

An advantageous composition in the form of an aqueous solution consistsessentially of the following components (% being % by weight of thetotal composition):

timolol in the form of its hemihydrate in an amount of 0.1 to 0.5% byweight, calculated as the free base,

polyacrylic acid in an amount of 0.04 to 0.4% by weight

glycerol in an amount of 0.5 to 2.5% by weight

sodium phosphates in an amount of 0.01 to 1.5% by weight,

a preservative in an amount of 0 to 0.02%, and

water, the viscosity of the composition being less than 800 centipoiseand the pH of the composition being 6.5 to 8.

According to the invention, the term "consisting essentially of" isintended to mean that the composition contains only or essentially onlythe components listed in connection therewith. The compositions mayhowever, in addition, contain substances, such as ophthalmologicallyacceptable adjuvants and additives of such a type and in such amounts asto have no essential influence on the characteristics of thecomposition.

The composition according to the invention is typically prepared inthree stages. In the first step the polymer is dispersed in sterilewater and sterilized by autoclaving. In the second step, the otheringredients, namely the active ingredient(s), inorganic salt(s),tonicity regulating agent(s), preservative(s) and any other additives,are dissolved in sterile water and sterilized by filtration on a filter(pore size e.g. 0.2 μm). In the third and last step the solutionprepared in the two steps are combined aseptically and mixed until theyform a homogenous solution with a low viscosity. The pH of the solutionis usually adjusted by adjusting the relative amounts of active agentand polymer. Thereafter the composition is packaged in multi- or unitdose form.

The following examples illustrate the invention in more detail, withoutlimiting the same.

EXAMPLE 1

The following composition was made:

    ______________________________________                                        Composition        (g)                                                        ______________________________________                                        S-Timolol hemihydrate                                                                            2.56                                                       Carbopol 941       0.95                                                       Sodium phosphate monobasic                                                                       0.08                                                       Sodium phosphate dibasic                                                                         1.80                                                       Glycerol           23.0                                                       Benzalkonium chloride                                                                            0.06                                                       Water for injection                                                                              to 1000 mL                                                 ______________________________________                                    

Carbopol 941 was dispersed in 300 mL sterile water at room temperature.The solution was sterilized in an autoclave. The autoclaved solution wascooled to room temperature (solution 1). Benzalkonium chloride,glycerol, sodium phosphate monobasic and dibasic and timolol hemihydratewere dissolved in 700 mL sterile water at room temperature andsterilized by filtration on a filter with a pore size of 0.2 μm(solution 2). In the final step the solutions prepared in the twoprevious steps (solution 1 and 2) were combined aseptically and mixeduntil they formed a homogenous low viscous solution. The pH of thesolution obtained was 7.4 and its viscosity was 440 centipoise (D=1.1s⁻¹). Thereafter the solution was packed in traditional eye dropbottles.

The viscosity vs. shear rate curve for the composition is shown inFIG. 1. It is to be noted that the shape of the curve shows stillnon-newtonian rheology despite the addition of salts.

EXAMPLE 2

The following composition was made:

    ______________________________________                                        Composition      (g)                                                          ______________________________________                                        S-Timolol hemihydrate                                                                          2.56                                                         Carbopol 941     0.85                                                         Sodium chloride  0.9                                                          Glycerol         20.0                                                         Benzalkonium chloride                                                                          0.06                                                         Water for injection                                                                            to 1000 mL                                                   ______________________________________                                    

The solution was prepared according to the Example 1. The pH of thesolution obtained was 6.9 and the viscosity of the solution was 380centipoise (D=1.1 s⁻¹). Viscosity vs. shear rate curve is shown in FIG.1.

EXAMPLE 3

The following composition was made:

    ______________________________________                                        Composition        (g)                                                        ______________________________________                                        S-Timolol hemihydrate                                                                            2.56                                                       Carbopol 981       1.4                                                        Sodium phosphate monobasic                                                                       0.62                                                       Sodium phosphate dibasic                                                                         2.85                                                       Glycerol           23.0                                                       Benzalkonium chloride                                                                            0.06                                                       Water for injection                                                                              to 1000 mL                                                 ______________________________________                                    

The solution was prepared according to the Example 1. The pH of thesolution obtained was 6.9 and the viscosity of the solution was 70centipoise (D=1.1 s⁻¹). Viscosity vs. shear rate curve is shown in FIG.1.

EXAMPLE 4

The following composition was made:

    ______________________________________                                        Composition        (g)                                                        ______________________________________                                        S-Timolol hemihydrate                                                                            1.0                                                        Carbopol 981       0.65                                                       Sodium phosphate monobasic                                                                       0.016                                                      Sodium phosphate dibasic                                                                         0.32                                                       Glycerol           23.0                                                       Benzalkonium chloride                                                                            0.06                                                       Water for injection                                                                              to 1000 mL                                                 ______________________________________                                    

The solution was prepared according to the Example 1. The pH of thesolution obtained was pH 6.6. The viscosity of the solution was 540centipoise (D=1.1 s⁻¹).

EXAMPLE 5

The following composition was made:

    ______________________________________                                        Composition        (g)                                                        ______________________________________                                        S-Timolol hemihydrate                                                                            2.56                                                       Carbopol 941       2.0                                                        Sodium phosphate monobasic                                                                       1.40                                                       Sodium phosphate dibasic                                                                         7.42                                                       Glycerol           16.0                                                       Benzalkonium chloride                                                                            0.06                                                       Water for injection                                                                              to 1000 mL                                                 ______________________________________                                    

The solution was prepared according to the Example 1. The pH of thesolution obtained was 6.9 and the viscosity was 600 centipoise (D=1.1s⁻¹).

EXAMPLE 6

The following composition was made:

    ______________________________________                                        Composition        (g)                                                        ______________________________________                                        S-Timolol hemihydrate                                                                            5.12                                                       Carbopol 981       3.0                                                        Sodium phosphate monobasic                                                                       2.0                                                        Sodium phosphate dibasic                                                                         10.0                                                       Glycerol           5.0                                                        Benzalkonium chloride                                                                            0.07                                                       Water for injection                                                                              to 1000 mL                                                 ______________________________________                                    

The solution was prepared according to the Example 1. The pH of thesolution obtained was 6.9 and the viscosity was 670 centipoise (D=1.1s^(-s)).

EXAMPLE 7

The following composition was made:

    ______________________________________                                        Composition        (g)                                                        ______________________________________                                        Clonidine (base)   1.25                                                       Carbopol 981       0.70                                                       Sodium phosphate monobasic                                                                       0.04                                                       Sodium phosphate dibasic                                                                         0.6                                                        Glycerol           23.0                                                       Benzalkonium chloride                                                                            0.06                                                       Water for injection                                                                              to 1000 mL                                                 ______________________________________                                    

The solution was prepared according to the Example 1. The pH of thesolution obtained was 7.0 and the viscosity was 540 centipoise (D=1.1s⁻¹).

EXAMPLE 8

The following composition was made:

    ______________________________________                                        Composition        (g)                                                        ______________________________________                                        Pilocarpine (base) 20.0                                                       Carbopol 981       3.0                                                        Sodium phosphate monobasic                                                                       10.6                                                       Sodium phosphate dibasic                                                                         0.53                                                       Glycerol           5.0                                                        Benzalkonium chloride                                                                            0.10                                                       Water for injection                                                                              to 1000 mL                                                 ______________________________________                                    

The solution was prepared according to the Example 1. The pH of thesolution obtained was 6.8 and the viscosity was 900 centipoise (D=1.1s⁻¹).

By leaving out from the formulations (Examples 1-8) the benzalkoniumchloride, corresponding unit-dose formulations were obtained.

Absorption of timolol into the rabbit eye (Study 1)

An ophthalmic formulation (Example 1), which is a typical example ofthis invention, was instilled into a rabbit eye (n=6). The concentrationof timolol in the aqueous humor was measured after 1/2 and 1 hours usingHPLC. The reference product contained the same amount of carbopol,timolol and preservative, benzalkonium chloride, but did not contain anyinorganic salt(s). The viscosity of the reference product was muchhigher (7300 centipoise, D=1.1 s⁻¹). The viscosity curves of theproducts are shown in FIG. 2.

The timolol concentrations in the aqueous humor in rabbits are shown inFIG. 3. According to FIG. 3, the absorption of timolol in rabbits eyewas equal despite the different viscosities.

Absorption of timolol into the rabbit eye (Study 2 and 3)

Timolol solutions were installed into a rabbit eye. The administeredtimolol solutions had the same pH and viscosity, but the solutionscontained different amounts of polyacrylic acid (Carbopol 941). Theconcentration of timolol in the aqueous humor was measured after 1/2 and1 hours using HPLC. The timolol concentrations in the aqueous humor inrabbits are shown in the FIG. 4 and 5. According to FIG. 4 and 5, theabsorption of timolol in rabbit eye depend on the concentration of thepolymer used.

Stability of the timolol-polvacrylic acid solution

An ophthalmic formulation (Example 1), which is a typical formulation ofthis invention, was stored at room temperature for 12 months. Theviscosity of the timolol-polyacrylic acid solution was measured afterdifferent time intervals with a Brookfield LVDV-III type viscometer atroom temperature. The viscosity vs. shear rate curves are shown in FIG.6. The results show that the viscosity of the timolol-polyacrylicacid-solutiom remained stable even after one year of storage.

We claim:
 1. Ophthalmic composition in the form of a topical aqueoussolution consisting essentially of:an ophthalmologically active agentcontaining basic groups, an ion sensitive, hydrophilic polymercontaining acidic groups in an amount of 0.004 to 1.5% by weight, atleast one salt selected from the group of inorganic salts and buffers ina total amount of from 0.01 to 2.0% by weight, a wetting agent in anamount of 0 to 3.0% by weight, a preservative in an amount of 0 to 0.02%by weight, as well as water,the ratio between salt and polymer beingsuch that the solution exhibits a viscosity of less than 1000centipoise, and the pH of the solution is between about 4.0 and about8.0.
 2. The composition of claim 1, wherein the polymer is present in anamount of from 0.01 to 0.8 by weight and is selected from the groupconsisting of carbopol 907, 910, 934, 934P, 940, 941, 971, 971P, 974,974P, 980 and
 981. 3. The composition of claim 1 wherein the wettingagent is glycerol.
 4. The composition of claim 3, wherein the amount ofglycerol is 0.5 to 2.5% by weight.
 5. The composition of claim 1 or 2,wherein the sale is selected from the group consisting of sodiumchloride, potassium chloride, sodium phosphates, sodium borate, sodiumacetate, sodium citrate and mixtures thereof.
 6. The composition ofclaim 1 or 2, wherein the viscosity is less than 800 centipoise.
 7. Thecomposition of claim 1 or 2, having a pH of 5.0 to 8.0.
 8. Thecomposition of claim 1, wherein the ophthalmologically active agent isselected from the group consisting of antiglaucoma agents,symphathoimimetic agents, sympatholytic agents, P-blockers, carbonicanhydrase inhibitors, antibiotics, antiinflammatoric agents,antiallergic agents and mixtures thereof.
 9. The composition of claim 8,wherein the active agent is selected from the group consisting ofbetaxolol, carteolol, levobunolol, metipranolol, pindolol, propranololand timolol, pilocarpine and mixtures thereof.
 10. The compositionaccording to claim 1, consisting essentially of:timolol hemihydrate inan amount of 0.01 to 0.5% by weight; polyacrylic acid in an amount of0.04 to 0.4% by weight; glycerol in an amount of 0.5 to 2.5% by weight,sodium phosphates in an amount of 0.01 to 1.5% by weight, a preservativein an amount of 0 to 0.02%, and waterthe viscosity of the solution beingless than 800 centipoise and the pH of the solution being 6.5 to 8.